1&#39;-substituted xanthene-9-spiro-4&#39;-piperidine derivatives

ABSTRACT

The disclosure relates to xanthene derivatives which possess analgesic activity, to processes for the manufacture of said derivatives and to pharmaceutical compositions containing them. Typical of the xanthene derivatives disclosed is 6-chloro-4-hydroxy-1&#39;-methylxanthene-9-spiro-4&#39;-piperidine.

This invention relates to xanthene derivatives which possess analgesicproperties.

According to the invention there is provided a xanthene derivative ofthe formula: ##STR1## wherein R¹ stands for

1. A HYDROGEN ATOM OR AN

2. ALKYL RADICAL OF 1 TO 10 CARBON ATOMS;

3. AN ALKENYL RADICAL OF 3 TO 10 CARBON ATOMS;

4. A HALOALKENYL RADICAL OF 3 TO 6 CARBON ATOMS;

5. AN ALKYNYL RADICAL OF 3 TO 6 CARBON ATOMS;

6. A CYCLOALKYLALKYL RADICAL OF 4 TO 7 CARBON ATOMS, OPTIONALLYSUBSTITUTED IN THE CYCLOALKYL NUCLEUS BY AN ARYL RADICAL OF 6 TO 10CARBON ATOMS OR BY ONE OR TWO ALKYL RADICALS OF 1 TO 3 CARBON ATOMS;

7. A PHENYL RADICAL;

8. AN ARYLALKYL RADICAL OF 7 TO 10 CARBON ATOMS, OPTIONALLY SUBSTITUTEDIN THE ARYL NUCLEUS BY ONE TO THREE HALOGEN ATOMS OR ALKYL RADICALS OF 1TO 3 CARBON ATOMS;

9. AN AROYLALKYL RADICAL OF 8 TO 12 CARBON ATOMS, OPTIONALLY SUBSTITUTEDIN THE ARYL NUCLEUS BY ONE TO THREE HALOGEN ATOMS OR ALKYL RADICALS OF 1TO 3 CARBON ATOMS;

10. A HYDROXYALKYL RADICAL OF 2 TO 5 CARBON ATOMS;

11. A DIALKYLAMINOALKYL RADICAL OF 4 TO 8 CARBON ATOMS;

12. A CARBAMOYLALKYL RADICAL OF 2 TO 8 CARBON ATOMS;

13. AN ALKYLCARBAMOYLALKYL RADICAL OF 3 TO 8 CARBON ATOMS;

14. A DIALKYLCARBAMOYLALKYL RADICAL OF 4 TO 8 CARBON ATOMS; OR

15. AN ALKANOYLALKYL RADICAL OF 3 TO 8 CARBON ATOMS; R², R³, R⁴ and R⁵,which may be the same or different, stand for

16. HYDROGEN ATOMS OR

17. HALOGEN ATOMS; OR FOR

18. ALKYL RADICALS OF 1 TO 5 CARBON ATOMS;

19. HALOALKYL RADICALS OF 1 TO 5 CARBON ATOMS;

20. ALKOXY RADICALS OF 1 TO 5 CARBON ATOMS;

21. ALKYLTHIO RADICALS OF 1 TO 5 CARBON ATOMS;

22. HYDROXY RADICALS;

23. THIOL RADICALS;

24. ALKANOYLAMINO RADICALS OF 1 TO 5 CARBON ATOMS;

25. ALKANOYLOXY RADICALS OF 1 TO 5 CARBON ATOMS;

26. AROYLOXY RADICALS OF 7 TO 10 CARBON ATOMS, OPTIONALLY SUBSTITUTED INTHE ARYL NUCLEUS BY ONE TO THREE HALOGEN ATOMS OR ALKYL RADICALS OF 1 TO3 CARBON ATOMS;

27. ARYLALKENOYLOXY RADICALS OF 9 TO 12 CARBON ATOMS;

28. HYDROXYALKYL RADICALS OF 1 TO 5 CARBON ATOMS;

29. ALKYLSULPHINYL RADICALS OF 1 TO 5 CARBON ATOMS; OR

30. ALKANESULPHONYLOXY RADICALS OF 1 TO 5 CARBON ATOMS;

And the pharmaceutically-acceptable acid-addition salts thereof.

It is to be understood that when R¹ is an alkenyl, haloalkenyl oralkynyl radical, the double or triple bond it contains is separated fromthe nitrogen atom of the spiropiperidine ring by at least one carbonatom, and when R¹ is a hydroxyalkyl or dialkylaminoalkyl radical, theoxygen or nitrogen atom it contains is separated from the nitrogen atomof the spiropiperidine ring by at least two carbon atoms.

The numbering system used in this specification to describe the positionof a substituent on the xanthene nucleus is as follows: ##STR2##

Reference to substitution at a particular position means substitution atthat numbered position in the xanthene nucleus as defined immediatelyabove.

A particular value for R¹ when it is an alkyl radical is such a radicalof 1 to 8 carbon atoms, for example a methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl or n-hexyl radical.

A particular value for R¹ when it is an alkenyl radical is such aradical of 3 to 7 carbon atoms, for example allyl, 2-methylprop-2-enylor 3-methylbut-2-enyl radical.

A particular value for R¹ when it is a haloalkenyl radical is such aradical of 3 or 4 carbon atoms, for example a 3-chloroprop-2-enylradical.

A particular value for R¹ when it is an alkynyl radical is such aradical of 3 or 4 carbon atoms, for example a propargyl radical.

A particular value for R¹ when it is a cycloalkylalkyl radical is acyclopropylmethyl or cyclobutylmethyl radical.

A particular value for R¹ when it is an arylalkyl radical is a benzyl orphenethyl radical.

A particular value for R¹ when it is an aroylalkyl radical is a3-(4-fluorobenzoyl)propyl radical.

A particular value for R¹ when it is a hydroxyalkyl radical is a2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-1-methylethyl radical.

A particular value for R¹ when it is a dialkylaminoalkyl radical is sucha radical of 4 to 6 carbon atoms, for example a 2-dimethylaminoethylradical.

A particular value for R¹ when it is a carbamoylalkyl radical is such aradical of 2 to 4 carbon atoms, for example a carbamoylmethyl radical.

A particular value for R¹ when it is an alkylcarbamoylalkyl radical issuch a radical of 3 to 5 carbon atoms, for example amethylcarbamoylmethyl radical.

A particular value for R¹ when it is a dialkylcarbamoylalkyl radical issuch a radical of 4 to 6 carbon atoms, for example adimethylcarbamoylmethyl radical.

A particular value for R¹ when it is an alkanoylalkyl radical is such aradical of 3 to 6 carbon atoms, for example an acetylmethyl radical.

A particular value for R², R³, R⁴ or R⁵ when it is a halogen atom is afluorine, chlorine or bromine atom.

A particular value for R², R³, R⁴ or R⁵ when it is an alkyl radical issuch a radical of 1 to 3 carbon atoms, for example a methyl radical.

A particular value for R², R³, R⁴ or R⁵ when it is a haloalkyl radicalis such a radical of 1 to 3 carbon atoms, for example a trifluoromethylradical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkoxy radical issuch a radical of 1 to 3 carbon atoms, for example a methoxy radical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkylthio radicalis such a radical of 1 to 3 carbon atoms, for example a methylthioradical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkanoylaminoradical is such a radical of 1 to 3 carbon atoms, for example anacetylamino radical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkanoyloxyradical is such a radical of 1 to 3 carbon atoms, for example an acetoxyradical.

A particular value for R², R³, R⁴ or R⁵ when it is an aroyloxy radicalis a 4-chlorobenzoyloxy radical.

A particular value for R², R³, R⁴ or R⁵ when it is an arylalkenoyloxyradical is such a radical of 9 or 10 carbon atoms, for example acinnamoyloxy radical.

A particular value for R², R³, R⁴ or R⁵ when it is a hydroxyalkylradical is such a radical of 1 to 3 carbon atoms, for example ahydroxymethyl radical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkylsulphinylradical is such a radical of 1 to 3 carbon atoms, for example amethylsulphinyl radical.

A particular value for R², R³, R⁴ or R⁵ when it is an alkanesulphonyloxyradical is such a radical of 1 to 3 carbon atoms, for example amethanesulphonyloxy radical.

Particular groups of compounds of the invention, each substituent beingdescribed by number as defined above, are as follows:

Those wherein R¹ is as defined above and R², R³, R⁴ and R⁵ stand forvalues 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 28, for examplehydrogen, fluorine, chlorine or bromine atoms or methyl,trifluoromethyl, methoxy, methylthio, hydroxy, thiol, acetylamino,acetoxy, 4-chlorobenzoyloxy, hydroxymethyl or 1-hydroxyethyl radicals,provided that when R² and R³ are both other than hydrogen they are thesame and when R⁴ and R⁵ are both other than hydrogen they are the same.

Further particular groups of compounds of the invention are as follows:

R¹ = 1 or 2

R² = 20, 21, 22, 23, 25 or 26 substituted at the 4-position

R³, r⁴, r⁵ = hydrogen

R¹ = 1 or 2

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R³, r⁴, r⁵ = hydrogen

R¹ = hydrogen, methyl or ethyl

R² = 20, 21, 22, 23, 25 or 26 substituted at the 4-position

R³, r⁴, r⁵ = hydrogen

R¹ = hydrogen, methyl or ethyl

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R³, r⁴, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = 17, 18, 19, 20, 21 or 28 substituted at the 2- or 3-position

R³, r⁴, r⁵ = hydrogen

R¹ = 2, 3, 6, 8, 9, 10, 11, 12, 13 or 14

R² = chlorine, bromine, methyl, trifluoromethyl, methoxy, methylthio or1-hydroxyethyl substituted at the 2-or 3-position

R³, r⁴, r⁵ = hydrogen

R¹ = 2 or 9

R² = chlorine, bromine, methyl, trifluoromethyl, methoxy, methylthio or1-hydroxyethyl substituted at the 2-or 3-position

R³, r⁴, r⁵ = hydrogen

R¹ = methyl or 3-(4-fluorobenzoyl)propyl

R² = chlorine, bromine, methyl, trifluoromethyl, methoxy, methylthio or1-hydroxyethyl substituted at the 2-or 3-position

R³, r⁴, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7-or 8-position

R³, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7-or 8-position

R³, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio,hydroxy or methylsulphinyl substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio orhydroxy substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7-or 8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio,hydroxy or methylsulphinyl substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = 2, 3, 4, 5 or 6

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio orhydroxy substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² =: 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R⁴ = 17, 18, 19, 20, 21 or 22 substituted at the 6-, 7-or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted in the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio,hydroxy or methylsulphinyl substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = 20, 21, 22, 23, 24, 25, 26 or 27 substituted at the 4-position

R⁴ = fluorine, chlorine, methyl, trifluoromethyl, methoxy, methylthio orhydroxy substituted at the 6-, 7- or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = methoxy, hydroxy or acetoxy substituted at the 4-position

R⁴ = fluorine, chlorine, methoxy, methylthio, hydroxy or methylsulphinylsubstituted at the 6-position or fluorine or chlorine substituted at the7- or 8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = methoxy, hydroxy or acetoxy substituted at the 4-position

R⁴ = fluorine, chlorine, methoxy, methylthio or hydroxy substituted atthe 6-position or fluorine or chlorine substituted at the 7- or8-position

R³, r⁵ = hydrogen

R¹ = methyl

R² = hydroxy, methoxy or acetoxy substituted at the 4-position

R³ = hydrogen

R⁴, r⁵ = fluorine or chlorine (same or different)

Particular compounds of the invention are described in the Examples andof those the preferred compound is that wherein

R¹ = methyl

R² = hydroxy substituted at the 4-position

R⁴ = chlorine substituted at the 6-position

R³, r⁵ = hydrogen

and the salts thereof as defined above.

A suitable pharmaceutically-acceptable acid-addition salt of theinvention is, for example, a hydrochloride, hydrobromide, phosphate orsulphate, or a citrate, acetate, maleate or oxalate.

The xanthene derivative of the invention may be manufactured by methodsknown in themselves for the manufacture of chemically analogouscompounds, R¹, R², R³, R⁴ and R⁵ having the meanings stated above, forexample:

a. for those compounds in which R¹ has a value other than those numbered1, 4, 5, 10, 12, 13 or 15 and R², R³, R⁴ and R⁵ have values other thanthose numbered 19, 22, 23, 24, 25, 26, 27, 28 or 30, reacting a compoundof the formula III: ##STR3## wherein R⁶, R⁷, R⁸ and R⁹ have the valuesstated above for R², R³, R⁴ and R⁵ respectively other than thosenumbered 19, 22, 23, 24, 25, 26, 27, 28 or 30 with a compound of theformula R¹⁰ N(CH₂ CH₂ X)₂ wherein R¹⁰ has the value stated above for R¹other than that numbered 1, 4, 5, 10, 12, 13 or 15 and wherein X is adisplaceable radical. X may be, for example, a displaceable halogenatom, for example a chlorine or bromine atom, or an arenesulphonyloxy oralkanesulphonyloxy radical, for example a toluene-p-sulphonyloxy ormethanesulphonyloxy radical. The reaction is preferably conducted in thepresence of a base, for example sodium methylsulphinylmethide, in adiluent or solvent, for example dimethyl sulphoxide, and is preferablyconducted in an inert atmosphere.

b. for those compounds in which R¹ has a value other than that numbered12, 13, 14 or 15 and R², R³, R⁴ and R⁵ have values other than thosenumbered 19, 24, 25, 26, 27 or 30, reducing a compound of the formulaIV: ##STR4## wherein R¹¹ has the value stated above for R¹ other thanthat numbered 12, 13, 14 or 15, R¹², R¹³, R¹⁴ and R¹⁵ have the valuesstated above for R², R³, R⁴ and R⁵ other than those numbered 19, 24, 25,26, 27 or 30 and wherein R¹⁶ and R¹⁷ stand for hydrogen atoms ortogether stand for an oxygen atom. The reduction may be carried out witha complex metal hydride, for example lithium aluminium hydride, in adiluent or solvent, for example diethyl ether or tetrahydrofuran, andmay be accelerated or completed by the application of heat, for exampleby heating to the boiling point of the diluent or solvent.

c. for those compounds in which R¹ has a value other than that numbered3, 4, 5, 10, 11, 12, 13 or 14 and R², R³, R⁴ and R⁵ have values otherthan those numbered 20, 23, 24, 25, 26, 27, 28 or 30, cyclisation of acompound of the formula V: ##STR5## wherein R¹⁶ has the value statedabove for R¹ other than that numbered 3, 4, 5, 10, 11, 12, 13 or 14 andR¹⁷, R¹⁸, R¹⁹ and R²⁰ have the values stated above for R², R³, R⁴ and R⁵other than those numbered 20, 23, 24, 25, 26, 27, 28 or 30. Thecyclisation may be carried out with a strong acid, for example sulphuricor polyphosphoric acid, and the reaction may be accelerated or completedby the application of heat, for example by heating to about 100° C.

d. for those compounds in which R¹ has a value other than that numbered11, 12, 13, 14 or 15 and R², R³, R⁴ and R⁵ have values other than thosenumbered 19, 25, 26 or 27, reaction of a compound of the formula VI:##STR6## wherein R²¹, R²², R²³ and R²⁴ have the values stated above forR², R³, R⁴ and R⁵ other than those numbered 19, 25, 26 or 27 with acompound of the formula R²⁵ NH₂ wherein R²⁵ has the value stated abovefor R¹ other than that numbered 11, 12, 13, 14 or 15. The reaction maybe conducted by heating the reactants in a diluent or solvent, forexample ethanol or xylene. Where a temperature higher than the boilingpoint of the diluent or solvent is required, the reaction may beconducted in a pressure vessel. Alternatively where the boiling point ofthe reactant of the formula R²⁵ NH₂ is sufficiently high, no diluent orsolvent may be required.

e. for those compounds in which R¹ is an alkyl or cycloalkylalkylradical, R² is a hydrogen atom or an alkyl radical and one of R³, R⁴ andR⁵ is a hydroxy, alkoxy, hydroxymethyl or thiol radical and theremaining two members of R³, R⁴ and R⁵ are hydrogen atoms, quenching ananion of the formula VII: ##STR7## wherein R²⁶ is an alkyl orcycloalkylalkye radical and R²⁷ is a hydrogen atom or an alkyl or alkoxyradical. The reaction may be conducted in a diluent or solvent, forexample hexane, in an inert atmosphere. The anion is quenched with areagent which gives rise to a hydroxy, alkoxy, hydroxymethyl or thiolradical, for example hydrogen peroxide, t-butyl perbenzoate,paraformaldehyde or sulphur respectively.

f. for those compounds in which R¹ ia an alkyl, cycloalkylalkyl orarylalkyl radical and R², R³, R⁴ and R⁵ have values other than thosenumbered 19, 24, 25, 26, 27 or 30, reducing a compound of the formulaVIII: ##STR8## wherein R¹², R¹³, R¹⁴ and R¹⁵ have the meanings statedabove and wherein R²⁸ is an alkanoyl, cycloalkylalkanoyl or arylalkanoylradical. The reduction may be carried out with a complex metal hydride,for example lithium aluminum hydride, in a diluent or solvent, forexample diethyl ether or tetrahydrofuran, and it may be accelerated orcompleted by the application of heat, for example by heating to theboiling point of the diluent or solvent.

g. for those compounds in which R¹ is a hydrogen atom and R², R³, R⁴ andR⁵ have values other than those numbered 21, 23, 24, 25, 26, 27 or 30,replacement by hydrogen of the alkyl or arylalkyl radical in a compoundof the formula IX: ##STR9## wherein R²⁹ is an alkyl or arylalkyl radicaland R³⁰, R³¹, R³² and R³³ have the values stated above for R², R³, R⁴and R⁵ other than those numbered 21, 23, 24, 25, 26, 27 or 30. When R²⁹is an α-arylalkyl radical, for example the benzyl radical, it may bereplaced by hydrogen by hydrogenolysis, for example by hydrogenation inthe presence of a palladium-on-charcoal catalyst in a diluent orsolvent. The hydrogen may be at atmospheric pressure or it may be at apressure of up to 10 atmospheres. When R²⁹ is an alkyl or arylalkylradical, for example a methyl, isopropyl or benzyl radical, it may bereplaced by hydrogen by treatment with an alkyl or aryl chloroformate,for example ethyl or phenyl chloroformate, followed by hydrolysis of thealkyl- or aryl-oxycarbonyl derivative thus obtained. The hydrolysis maybe carried out by heating with a base, for example sodium or potassiumhydroxide, in a diluent or solvent, for example ethanol or aqueousethanol.

h. for those compounds in which R¹ is other than a hydrogen atom and R²,R³, R⁴ and R⁵ have values other than those numbered 21, 22, 23, or 24,reaction of a compound of the formula X: ##STR10## wherein R³⁴, R³⁵, R³⁶and R³⁷ have the values stated above for R², R³, R⁴ and R⁵ other thanthose numbered 21, 22, 23, or 24, with a compound of the formula R³⁸ -Ywherein R³⁸ has the values stated above for R¹ other than a hydrogenatom and Y is a displaceable halogen atom. Y may be, for example, achlorine or bromine atom and the reaction may be conducted in thepresence of a base, for example sodium bicarbonate or sodium hydride, ina diluent or solvent, for example dimethyl formamide. The reaction maybe accelerated or completed by the application of heat, for example byheating to the boiling point of the diluent or solvent.

i. for those compounds in which R¹ is a haloalkenyl radical and R², R³,R⁴ and R⁵ have the values other than those numbered 20, 21, 25, 26, 27or 30, addition of a hydrogen halide to the triple bond in a compound ofthe formula XI: ##STR11## wherein R³⁹ is an alkynyl radical and R⁴⁰,R⁴¹, R⁴² and R⁴³ have the values stated above for R², R³, R⁴ and R⁵other than those numbered 20, 21, 25, 26, 27 or 30. the hydrogen halidemay be, for example, hydrogen chloride and it may be added to the triplebond by reaction with pyridine hydrochloride,

j. for those compounds in which R¹ has a value other than that numbered3, 4 or 5 and in which at least one of R², R³, R⁴ and R⁵ is a hydroxyradical and the remaining members of R², R³, R⁴ and R⁵ have values otherthan that numbered 27, replacement by hydrogen of the benzyl group in acompound of the formula XII: ##STR12## wherein R⁴⁴ has the value statedabove for R¹ other than that numbered 3, 4 or 5 and at least one of R⁴⁵,R⁴⁶, R⁴⁷ and R⁴⁸ is a benzyloxy radical and the remaining members ofR⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ have the values stated above for R², R³, R⁴ and R⁵other than that numbered 27. The benzyl group may be replaced byhydrogen by reaction with hydrogen in the presence of apalladium-on-charcoal catalyst or by reaction with an acid, for exampleaqueous ethanolic hydrochloric acid.

k. for those compounds in which R¹ has a value other than that numbered5 and in which at least one of R², R³, R⁴ and R⁵ is a hydroxy radicaland the remaining members of R², R³, R⁴ and R⁵ have values other thanthose numbered 20, 21, 25, 27 or 30, replacement by hydrogen of thealkyl part of the alkoxy radical in a compound of the formula XIII:##STR13## wherein R⁴⁹ has the value stated above for R¹ other than thatnumbered 5 and in which at least one of R⁵⁰, R⁵¹, R⁵² and R⁵³ is analkoxy radical and the remaining members of R⁵⁰, R⁵¹, R⁵² and R⁵³ havethe values stated above for R², R³, R⁴ and R⁵ other than those numbered20, 21, 25, 27 or 30. The reaction may be carried out with an acid, forexample with HBr in acetic acid at reflux or with aqueous 48% w/v HBr atreflux; with boron tribromide in a solvent such as methylene chloride;with pyridine hydrochloride, for example by heating at 200° C.; withsodium ethanethiolate or sodium thiophenoxide, for example by heating ina solvent such as dimethyl formamide at 100°-150° C. under argon; orwith lithium iodide.

l. for those compounds in which at least one of R², R³, R⁴ and R⁵ is ahydroxy radical and the remaining members of R², R³, R⁴ and R⁵ havevalues other than those numbered 25, 26, or 27, hydrolysis of theacyloxy radical in a compound of the formula XIV: ##STR14## wherein atleast one of R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ is an acyloxy radical and theremaining members of R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ have the values stated abovefor R², R³, R⁴ and R⁵ other than those numbered 25, 26 or 27. Theacyloxy radical may be such a radical of up to 10 carbon atoms, forexample an acetoxy or benzoyloxy radical. The hydrolysis may be carriedout with a dilute acid or base, for example 3NHCl.

m. for those compounds in which R¹ has a value other than that numbered3, 4, 5, 7, 8, 9 or 15 and at least one of R², R³, R⁴ and R⁵ is ahalogen atom and the remaining members of R², R³, R⁴ and R⁵ have valuesother than those numbered 21, 23 or 27, halogenation of a compound ofthe formula XV: ##STR15## wherein R⁵⁸ has the value stated above for R¹other than that numbered 3, 4, 5, 7, 8, 9 or 15 and R⁵⁹, R⁶⁰, R⁶¹ andR⁶² have the values stated above for R², R³, R⁴ and R⁵ other than thosenumbered 21, 23 or 27, at least one being hydrogen. The halogenation maybe carried out using a molecular halogen, for example bromine, in adiluent or solvent such as chloroform, or by using an N-halo derivativesuch as N-chlorosuccinimide.

n. for those compounds in which R¹ has a value other than that numbered1 or 10, at least one of R², R³, R⁴ and R⁵ has a value numbered 25, 26,27 or 30 and the remaining members of R², R³, R⁴ and R⁵ have valuesother than those numbered 22, 23 or 28, reaction of a compound of theformula XVI: ##STR16## wherein R⁶³ has the value stated above for R¹other than that numbered 1 or 10, at least one of R⁶⁴, R⁶⁵, R⁶⁶ and R⁶⁷is a hydroxy radical and the remaining members of R⁶⁴, R⁶⁵, R⁶⁶ and R⁶⁷have the values stated above for R², R³, R⁴ and R⁵ other than thosenumbered 22, 23 or 28, with an alkanoic, arylalkanoic, arylalkenoic oralkanesulphonic acid, or with an acylating agent derived therefrom. Theacid may be, for example, acetic acid, p-chlorobenzoic acid, cinnamicacid or methanesulphonic acid and the acylating agent derived therefrommay be, for example, the corresponding acid chloride or anhydride. Thereaction is preferably carried out in a basic solvent such as pyridine.

o. for those compounds in which R¹ has a value other than that numbered1 or 10, at least one of R², R³, R⁴ and R⁵ is an alkanoylamino radicaland the remaining members of R², R³, R⁴ and R⁵ have values other thanthose numbered 22, 23 or 28, reaction of a compound of the formula XVII:##STR17## wherein R⁶³ has the value stated above, at least one of R⁶⁸,R⁶⁹, R⁷⁰ and R⁷¹ is an amino radical and the remaining members of R⁶⁸,R⁶⁹, R⁷⁰ and R⁷¹ have the values stated above for R², R³, R⁴ and R⁵other than those numbered 22, 23 or 28, with an alkanoic acid or anacylating agent derived therefrom. The reactant may be, for example,acetic acid or the corresponding acid chloride or anhydride. Thereaction is preferably carried out in a diluent or solvent, for exampleether.

p. for those compounds in which R¹ is an alkyl radical, heating acompound of the formula XVIII: ##STR18## wherein R⁷² is an alkyl radicaland Z is a chlorine, bromine or iodine atom. When R⁷ is a methylradical, the reaction is conveniently carried out by heating to 200° C,in vacuo.

q. for those compounds in which at least one of R², R³, R⁴ and R⁵ is analkylsulphinyl radical and the remaining members of R², R³, R⁴ and R⁵have values other than that numbered 21 or 23, oxidation of a compoundof the formula XIX: ##STR19## wherein at least one of R⁷³, R⁷⁴, R⁷⁵ andR⁷⁶ is an alkylthio radical and the remaining members of R⁷³, R⁷⁴, R⁷⁵and R⁷⁶ have the values stated above for R², R³, R⁴ and R⁵ other thanthat numbered 23. The reaction may be carried out with a mild oxidisingagent such as sodium periodate, hydrogen peroxide or iodobenzenedichloride.

r. for those compounds wherein R¹ is an aroylalkyl or alkanoylalkylradical and R², R³, R⁴ and R⁵ have values other than those numbered 25,26 or 27, hydrolysis of a compound of the formula XX: ##STR20## whereinR⁷⁷ is a ketal derived from an aroylalkyl or alkanoylalkyl radical andR⁷⁸, R⁷⁹, R⁸⁰ and R⁸¹ have the values stated above for R², R³, R⁴ and R⁵other than those numbered 25, 26 or 27. The ketal may, for example, be adimethyl or ethylene ketal. The hydrolysis is preferably carried outwith a dilute mineral acid, for example by warming with 3N aqueous HC1.

The xanthene derivative of the invention may be converted into apharmaceutically-acceptable acid-addition salt by conventional means.

The starting materials for use in the processes of the invention may beprepared, from known compounds, as described in the Examples. Thefollowing summary illustrates the general reactions involved.

The starting material of the formula III for use in process (a) may beprepared by reaction of the appropriate 2-chlorobenzoic acid with theappropriate phenol as described in Example 32. The resulting acid iscyclised to the corresponding xanthone as described in Example 33, andthe xanthone is reduced to the corresponding xanthene as described inExample 34. The preparation of 2-fluoro-5-methoxyxanthone is describedin Example 35.

The starting material of the formula IV for use in process (b) may beprepared by dialkylation of the appropriate xanthene with 2-chloroethylvinyl ether. The product is oxidised with chromic acid to give thespiro-4'-tetrahydropyran-2'-one which is reacted with the appropriateamine to give the corresponding N-substitutedspiro-4'-piperidine-2'-one. Alternatively the appropriate xanthene maybe dialkylated with allyl bromide, the resulting 9,9-diallyl derivativeoxidised with potassium permanganate/sodium metaperiodate and theresulting diacid cyclised to the corresponding 6-membered anhydride withacetic anhydride. Reaction with the appropriate amine then gives thecorresponding monoacid-monoamide which is thereafter cyclised withacetic anhydride to give the N-substitutedspiro-4'-piperidin-2',6'-dione.

The starting material of the formula V for use in process (c) may beprepared by reaction of the anion derived from the appropriate diphenylether with the appropriate N-substituted 4-piperidone. The anion may beformed by reaction with butyl lithium.

The starting material of the formula VI for use in process (d) may beprepared by hydrolysis of the divinyl ether of the appropriate9,9-bis(2-hydroxyethyl)xanthene followed by reaction of the resultingdiol with a reagent which replaces OH with a displaceable radical, forexample a halogenating agent or methanesulphonyl chloride.

The anion of the formula VII used as starting material in process (e)may be prepared by abstraction of a proton from the correspondingneutral xanthene derivative, for example with butyl lithium.

The starting material of the formula VIII for use in process (f) may beprepared by reacting the free NH compound with the appropriatecarboxylic acid or acylating agent derived therefrom.

The starting material of the formula XVII for use in process (o) may beprepared by employing process (e) and quenching the anion withhydroxylamine methyl ether. Alternatively the appropriate aminoderivative can be prepared using the route described in Example 35 and34 to prepare the appropriate nitroxanthene. The spiropiperidine ringcan then be formed using process (a) or (d) and the nitro groupsubsequently reduced to an amino group.

The starting material of the formula XVIII for use in process (p) may beprepared by treatment of the dimethanesulphonate ester of theappropriate 9,9-bis(2-hydroxyethyl)-xanthene with the appropriatedialkylamine followed by treatment of the resulting quaternarymethanesulphonate in an ion-exchange column.

The starting material of the formula XIX for use in process (q) may beobtained by repeating process (h) using the appropriate alkylatingagent.

The preparations of specific starting materials are described inter aliain Examples 2, 3, 7, 10, 14, 17, 19, 21, 22, 24, 27 and 29, and also inExamples 32-35.

The compounds of the invention have analgesic activity in warm-bloodedanimals. This is demonstrated by activity in a number of standard testsfor detecting analgesic activity, for example the mouse writhing test(Collier et al., Brit. J. Pharmac. Chemother., 1968, 32, 295; Whittle,Brit. J. Pharmac. Chemother., 1964, 22, 246) and the mouse tail cliptest (Bianchi and Franceschini, Brit. J. Pharmac. Chemother., 1954, 9,280). These tests are carried out as follows:

Tail clip test

10 Female mice of bodyweight approximately 20 g. each are dosedsubcutaneously with the compound under test. Twenty minutes later themice are placed in a plastic arena (30 cm. diameter) and an artery clipis placed on the tail at a distance of 1 cm. from the rump. If anindividual mouse does not respond to the painful stimulus of the clipwithin a 10 second period, it is recorded as analgesed. In this way 50%analgesia corresponds to 5 mice in 10 showing a negative response to theclip.

Writhing test

A painful stimulus is produced by injection of a 0.25% v/v aqueoussolution of acetic acid or a 0.03% w/w aqueous solution of acetylcholineinto the peritoneum of a female mouse. The characteristic response tothis pain is an abdominal constriction in conjunction with a stretchingof the body.

Acetic Acid method

Of 12 20 g. female mice, 6 are dosed either subcutaneously or orallywith the compound under test and the remaining 6 act as controls. Twentyminutes later all 12 mice receive an injection of the acetic acidsolution (0.4 ml.) and are then placed into a plastic container dividedinto twelve compartments. The number of writhes of each mouse are thenrecorded over a 15 minute period starting 3 minutes after injection ofthe agent. The total number of writhes recorded for the treated groupare then totalled and compared with the total found for the controlgroup. The results are expressed as % analgesia as follows: ##EQU1##

Acetylcholine method

Of 12 20 g. female mice, 6 are dosed either subcutaneously or orallywith the compound under test and the remaining 6 act as controls. Thirtyminutes later all the 12 mice receive an intraperitoneal injection of0.2 ml. of the acetylcholine solution, and are placed on a plasticplatform (30 cm. diameter). Mice which do not writhe during the minuteimmediately after the injection are said to be analgesed. The resultsare expressed as % analgesia as follows: ##EQU2## (On averageapproximately 95% of controls respond to the acetylcholine challenge)

All the compounds exemplified in this specification are active on atleast one of these standard tests at a dose of equal to or less than 100mg./kg. of the free base. The compound of the invention6-chloro-4-hydroxy-1'-methylxanthene-9-spiro-4'-piperidine has an oralLD₅₀ in mice of greater than 200 mg./kg. The LD₅₀ of the same compoundwhen dosed intravenously is greater than 25 mg./kg. Other LD₅₀ valuesfor compounds of the invention when dosed intravenously are as follows:

    ______________________________________                                        R.sup.1 R.sup.2 R.sup.3   R.sup.4 LD.sub.50 (mg./kg.)                         ______________________________________                                        4-OAc   H       6-Cl      H       >35                                         4-OAc   H       6-SMe     H       >40                                         4-OH    H       8-F       H       >20                                         4-OAc   H       6-OMe     H       >20                                         ______________________________________                                    

Within the analgesics of the present invention, at least foursub-classes can be identified:

1. Compounds in which R², R³, R⁴ and R⁵ are other than values 20, 21,22, 23, 24, 25, 26 or 27 substituted at the 4- or 5-position areneuroleptic analgesics, that is analgesics of the methotrimeprazinetype, having a strong sedative component.

2. Compounds in which R¹ is a hydrogen atom or a methyl or ethylradical, R² has value 20, 21, 22, 23, 24, 25, 26 or 27 substituted atthe 4-position and R³, R⁴ and R⁵ are hydrogen atoms are narcoticanalgesics, that is analgesics of the morphine type with a range ofactivities from codeine to morphine.

3. Compounds in which R¹ is other than hydrogen, a methyl or ethylradical, R² has value 20, 21, 22, 23, 24, 25, 26 or 27 substituted atthe 4-position and R³, R⁴ and R⁵ are hydrogen atoms are partial agonistanalgesics, that is analgesics, of the pentazocine type, which partiallyantagonise the effect of morphine.

4. Compounds in which R¹ is hydrogen or methyl, R² has value 20, 21, 22,23, 24, 25, 26 or 27 substituted at the 4-position, R⁴ has value 17, 18,19, 20, 21, 22 or 29 substituted at the 6-, 7- or 8-position and R³ andR⁵ are hydrogen atoms have varying mixtures of analgesic and sedativeproperties.

According to a further feature of the invention there is provided apharmaceutical composition which comprises as active ingredient axanthene derivative of the invention in association with a non-toxicpharmaceutically-acceptable diluent or carrier.

The pharmaceutical composition may be, for example, in a form suitablefor oral, parenteral or rectal administration, for which purposes it maybe formulated by means known to the art into the form of, for example,tablets, capsules, aqueous or oily solutions or suspensions, emulsions,sterile injectable aqueous or oily solutions or suspensions, dispersiblepowders or suppositories.

The pharmaceutical composition of the invention may also contain, inaddition to the xanthene derivative, one or more known drugs selectedfrom other analgesic agents, for example aspirin, paracetamol,phenacetin, codeine, pethidine, and morphine, anti-inflammatory agents,for example naproxen, indomethacin and ibuprofen, neuroleptic agentssuch as chlorpromazine, prochlorperazine, trifluoperazine andhaloperidol and other sedative drugs and tranquillisers such aschlordiazepoxide, phenobarbitone and amylobarbitone.

A preferred pharmaceutical composition of the invention is one suitablefor oral administration in unit dosage form, for example tablets andcapsules, which contain between 1 and 200 mg. of active ingredient, orone suitable for intravenous, intramuscular or subcutaneous injection,for example a sterile aqueous solution containing between 1 and 50mg./ml. of active ingredient.

The pharmaceutical composition of the invention will normally beadministered to man for the treatment or prevention of pain at such adose that each patient receives an oral dose of between 30 mg. and 300mg. of active ingredient, an intramuscular or subcutaneous dose ofbetween 30 and 150 mg. of active ingredient or an intravenous dose ofbetween 15 and 75 mg. of active ingredient, the composition beingadministered 2 or 3 times per day.

The invention is illustrated, but not limited, by the following Examplesin which Examples 32 to 35 illustrate the preparation of startingmaterials:

EXAMPLE 1

A solution of xanthene (9.1 g.) in dimethyl sulphoxide (75 ml.) is addeddropwise over 20 minutes at room temperature to a solution of sodiummethylsulphinylmethide [prepared in the usual way from sodium hydride (8g. of a 60 % dispersion in mineral oil) and dimethyl sulphoxide (100ml.)] with stirring in an atmosphere of nitrogen. The blood-red mixtureis stirred at room temperature for a further 30 minutes, cooled to 0°C., and a solution of N-methyldi-(2-chloroethyl)amine (9.6 g.) indimethyl sulphoxide (20 ml.) is then added dropwise during 15 minutes,keeping the temperature below 20° C. Water (500 ml.) is added to the nowcolourless mixture, and the mixture is extracted three times with ether.The combined ether extracts are dried over MgSO₄, evaporated to drynessand the gummy residue (12.2 g.) is chromatographed on basic alumina(Brockmann Grade III), eluting with increasing concentrations ofchloroform in light petroleum (b.p. 60-80° C.). Elution with 5%chloroform in light petroleum gives, on evaporation of the solvent, agum which is dissolved in ether and treated with ethereal hydrochloricacid. The solid is recrystallised from ethanol-ether to give1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 220°-222° C.

EXAMPLE 2

A mixture of 1'-methylxanthene-9 -spiro-4'-piperidin-2'-one (50 mg.),lithium aluminium hydride (25 mg.) and dry tetrahydrofuran (15 ml.) isheated under reflux for 3 hours. Dilute sodium hydroxide solution isadded, and the mixture is filtered through diatomaceous earth. Thetetrahydrofuran is removed from the filtrate by evaporation underreduced pressure, and the aqueous residue is extracted with ether. Theethereal extract is dried over MgSO₄ and treated with etherealhydrochloric acid. The solid is recrystallised from ethanol-ether togive 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p.220-222° C.

The 1'-methylxanthene-9-spiro-4'-piperidin-2'-one used as startingmaterial may be obtained as follows:

A solution of xanthene (18.2 g.) in dimethyl sulphoxide (150 ml.) isadded dropwise over 20 minutes at room temperature to a solution ofsodium methylsulphinylmethide [prepared in the usual way from sodiumhydride (12 g. of a 60% dispersion in mineral oil) and dimethylsulphoxide (150 ml.)] with stirring in an atmosphere of nitrogen. Theblood-red mixture is stirred at room temperature for a further 30minutes, cooled to 10° C., and 2-chloroethyl vinyl ether (21.3 g.) isthen added dropwise during 30 minutes. Water (750 ml.) is added to thenow colourless mixture, and the mixture is extracted three times withether. The combined ether extracts are dried over MgSO₄ and evaporatedto dryness. The residue of 9,9-bis(2'-vinyloxyethyl)xanthene (28.0 g.)is dissolved in acetone (150 ml.) and treated with excess Jones reagent(chromic acid in acetone) at 10° C. Methanol is then added, and thesolvent is evaporated. To the residue water is added, and the mixture isextracted three times with ethyl acetate. The combined extracts arewashed with saturated sodium hydrogen carbonate solution, then withwater, dried over MgSO₄ and evaporated to dryness. The solid residue isrecrystallised from ethanol to givexanthene-9-spiro-4'-tetrahydropyran-2'-one, m.p. 156°-159° C.

A mixture of xanthene-9-spiro-4'-tetrahydropyran-2'-one (0.5 g.) andmethylamine (5 ml.) is heated at 250° C. for 4 hours in a steel bomb.The gummy residue (0.52 g.) is chromatographed on silica gel, elutingwith increasing concentrations of chloroform in light petroleum (b.p.60°-80° C.). Elution with 25% chloroform in light petroleum gives, onevaporation of the solvent, a solid residue which is recrystallised fromethanol to give 1'-methylxanthene-9-spiro-4'-piperidin-2-one, m.p.158°-159° C.

EXAMPLE 3

A mixture of 9,9-di(2'-methanesulphonyloxyethyl)-xanthene (0.21 g.) andphenethylamine (0.36 g.) is heated on the steam-bath under nitrogen for20 hours. Ether is added, an insoluble solid is filtered off and thefiltrate is treated with ethereal hydrochloric acid. The precipitate isfiltered off, washed with water, and crystallised from ethanol-ether togive 1'-phenethylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 275°C. (with decomposition).

The 9,9-di(2'-methanesulphonyloxyethyl)xanthene used as startingmaterial may be prepared as follows:

A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as inExample 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.)is heated on the steambath with vigorous stirring for 5 hours. Thecooled mixture is extracted three times with ether and the combinedextracts are dried over MgSO₄ and evaporated to dryness. The solidresidue is recrystallised from chloroform-light petroleum (b.p. 60°-80°C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C.Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in drypyridine (5 ml.) with stirring. The mixture is allowed to stand at roomtemperature for 20 hours and is then poured into a mixture of 3Nhydrocholoric acid (20 ml.) and ice (10 g.), and the resulting mixtureis extracted with ethyl acetate. The ethyl acetate extract is washedwith 3N hydrochloric acid and water, dried over MgSO₄, and evaporated todryness. The solid residue is recrystallised from acetone-lightpetroleum (b.p. 60°-80° C.) to give9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.

EXAMPLE 4

1'-Methyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (1.0g.) in a solution of 45% w/v hydrobromic acid in glacial acetic acid (10ml.) is heated under reflux for 2 hours. The solution is basified withsodium bicarbonate, diluted with water and extracted with chloroform.The chloroform extract is washed with water, dried over MgSO₄, andevaporated to dryness. The residue is recrystallised fromtoluene-petroleum ether (b.p. 60°-80° C.) to give1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 171°-173° C.

The 1'-methyl-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride usedas starting material may be obtained by the method described in Example1 using an equivalent amount of 4-methoxyxanthene instead of xanthene.The product is recrystallised from ethanol-ether and has m.p. 234°-236°C.

EXAMPLE 5

1'-Methyl-4-hydroxyxanthene-9-spiro-4'-piperidine hydrochloride (0.3 g.)in dry pyridine (10 ml.) is treated with excess acetic anhydride for 12hours at room temperature. Pyridine and acetic anhydride are removed invacuo and the residue dissolved in chloroform and treated with etherealhydrochloric acid. The solvent is removed and the residue recrystallisedfrom isopropanol-light petroleum to give1'-methyl-4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p.216°-220° C.

EXAMPLE 6

The process described in Example 1 is repeated using the equivalentamount of the appropriate substituted xanthene as starting materialinstead of xanthene. The following compounds are thus prepared:

    ______________________________________                                         ##STR21##                                                                    R.sup.1  R.sup.2    Salt       m.p.(° C.)                              ______________________________________                                        Me       2-Cl       HCl        238                                            Me       4-Cl       HCl        196-197                                        Me       2-Me       HCl        230                                            Me       2-CF.sub.3 HCl        305-306                                        Me       3-OMe      Maleate    141-143                                        ______________________________________                                    

EXAMPLE 7

A mixture of 4-methoxy-9,9-di(2'-methanesulphonyloxyethyl)xanthene (4.7g.) and a 33% (w/v) solution of ethylamine in ethanol (15 ml.) is heatedin a carius tube at 150° C. for 3 hours. Water is added to the cooledmixture and the ethanol is evaporated off. The mixture is extracted withether and the ether extract is washed with saturated potassium carbonatesolution and water, dried with MgSO₄ and treated with etherealhydrochloric acid. The gummy residue is crystallised from ethanol-etherto give 1'-ethyl-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride,m.p. 222°-224° C.

The above process is repeated using equivalent amounts of theappropriate xanthene and amine as starting materials. The followingcompounds are thus obtained:

    __________________________________________________________________________     ##STR22##                                                                    R.sup.1   R.sup.2                                                                           Salt                                                                              m.p.(° C.)                                                                   Solvent                                               __________________________________________________________________________    CH.sub.2 CH.sub.3                                                                       H   HCl 247-248                                                                             ethanol-ether                                         CH.sub.2 CH.sub.2 CH.sub.3                                                              H   HCl 269-272                                                                             ethanol-ether                                          ##STR23##                                                                              H   HCl 244-246                                                                             ethanol-ether                                         CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     H   HCl 268-270                                                                             ethanol-ether                                         CH.sub.2 CHCH.sub.2                                                                     H   HCl 232-235                                                                             ethanol-ether                                         (CH.sub.2).sub.4 CH.sub.3                                                               H   HCl 265-270                                                                             ethanol-ether                                         (CH.sub.2).sub.5 CH.sub.3                                                               H   HCl 260-264                                                                             ethanol-ether                                          ##STR24##                                                                              H   HCl 242-245                                                                             ethanol-ether                                          ##STR25##                                                                              H   HCl 265-270                                                                             ethanol-ether                                          ##STR26##                                                                              H   HCl 258-261                                                                             ethanol-ether                                         CH.sub.2 CH.sub.2 CH.sub.3                                                              OCH.sub.3                                                                         HCl 254-256                                                                             ethanol-ether                                         CH.sub.2 CHCH.sub.2                                                                     OCH.sub.3                                                                         HCl 212-214                                                                             ethanol-ether                                          ##STR27##                                                                              OCH.sub.3                                                                         HCl 228-230                                                                             ethanol-ether                                          ##STR28##                                                                              OCH.sub.3                                                                         HCl 215-217                                                                             ethyl acetate- methanol                               CH.sub.2 CH.sub.2 OH                                                                    OCH.sub.3                                                                         oxalate                                                                           190-192                                                                             ethyl acetate- methanol                                ##STR29##                                                                              OCH.sub.3                                                                         oxalate                                                                           235 (decomp.)                                                                       ethyl acetate- methanol                                ##STR30##                                                                              OCH.sub.3                                                                         oxalate                                                                           226-228                                                                             ethyl acetate- methanol                                ##STR31##                                                                              OCH.sub.3                                                                         oxalate                                                                           222-226                                                                             ethyl acetate- methanol                                ##STR32##                                                                              OCH.sub.3                                                                         oxalate                                                                           212 (decomp.)                                                                       ethyl acetate- methanol                                ##STR33##                                                                              OCH.sub.3                                                                         oxalate                                                                           228 (decomp.)                                                                       methanol-ether                                         ##STR34##                                                                              OCH.sub.3                                                                         oxalate                                                                           205 (decomp.)                                                                       methanol-ether                                         ##STR35##                                                                              OCH.sub.3                                                                         oxalate                                                                           200 (decomp.)                                                                       methanol-ether                                         ##STR36##                                                                              OCH.sub.3                                                                         HCl 241-242                                                                             ethyl acetate- methanol                                ##STR37##                                                                              OCH.sub.3                                                                         Free base                                                                         142-144                                                                             --                                                     ##STR38##                                                                              OCH.sub.3                                                                         oxalate                                                                           192 (decomp.)                                                                       methanol-ether                                        __________________________________________________________________________

The 4-methoxy-9,9-di(2'-methanesulphonyloxyethyl)-xanthene used asstarting material may be prepared by repeating the second part ofExample 2, and the second and third parts of Example 3 using4-methoxyxanthene as starting material and there is thus obtained4-methoxy-9,9-bis(2'-vinyloxyethyl)xanthene, m.p. 138° C.,4-methoxy-9,9-bis(2'-hydroxyethyl)xanthene, m.p. 140°-142° C. and4-methoxy-9,9-bis(2'-methanesulphonyloxyethyl)xanthene, m.p. 152°-154°C. respectively.

EXAMPLE 8

A solution of 1'-benzyl-4-methoxyxanthene-9-spiro-4'-piperidinehydrochloride (3.0 g.) in absolute ethanol (100 ml.) ishydrogenatedusing 5% palladium on carbon catalyst, at 4 atmospherespressure and 50° C. The catalyst is filtered off and the solventevaporated to dryness. The residue is crystallised from ethanol-ether togive 4-methoxyxanthene-9-spiro-4'-piperidine, m.p. 214°-216° c.

EXAMPLE 9

A mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.),1-bromo-3-methylbut-2-ene (1.15 g.), sodium bicarbonate (0.59 g.) anddimethylformamide (20 ml.) is heated under reflux for 4 hours. Themixture is cooled, poured into water and extracted with chloroform. Thechloroform extract is washed with water, dried with MgSO₄ and evaporatedto give a gummy residue. The residue is dissolved in isopropanol andtreated with ethereal hydrochloric acid. The residue is recrystallisedfrom isopropanol-ether to give1'-(3-methylbut-2-enyl)-4-methoxyxanthene-9-spiro-4'-piperidinehydrochloride, m.p. 247°-249° C.

EXAMPLE 10

A mixture of1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (5.3 g.),lithium aluminium hydride (4.5 g.) and dry tetrahydrofuran (200 ml.) isheated under reflux for 4 hours. Water (4.5 ml.), 3N sodium hydroxidesolution (4.5 ml.) and water (13.5 ml.) are added and the mixturefiltered. The tetrahydrofuran is removed by evaporation. The gummyresidue is dissolved in ether and treated with ethereal hydrochloricacid. The solid is recrystallised from ethanol-ether to give1'-cyclopropylmethyl-4-methoxyxanthene-9-spiro-4'-piperidinehydrochloride, m.p. 228°-230° C. The1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine used asstarting material may be prepared as follows:

A solution of cyclopropane carboxylic acid chloride (1.2 ml.) inmethylene chloride (10 ml.) is added dropwise with stirring to a mixtureof 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.) and triethylamine(1.6 ml.) in methylene chloride (40 ml.) at 5° C. The mixture is allowedto reach room temperature and stirred overnight. The mixture is washedwith 3N hydrochloric acid, 3N sodium hydroxide solution and water, driedMgSO₄ and the methylene chloride evaporated to dryness, to give1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (I.R.amide band 1620 cm.⁻ ¹ ; t.l.c. -- single spot) which is used withoutfurther purification.

EXAMPLE 11

The demethylation process described in Example 4 is repeated, eitherusing the method described in Example 4 or by one of the methodsdescribed below, and using the appropriate methoxyxanthene derivative asstarting material in place of1'-methyl-4-methoxyxanthene-9-spiro-4'-piperidine. The followingcompounds are thus prepared:

    __________________________________________________________________________     ##STR39##                                                                    R.sup.1       R.sup.2                                                                           R.sup.3                                                                          Method                                                                            Salt                                                                              m.p. (° C.)                                                                  Solvent                                    __________________________________________________________________________    H             H   OH A   HCl >300  ethanol-ether                              CH.sub.2 CH.sub.3                                                                           H   OH C   Free                                                                              164-166                                                                             ether-P.E.                                                          base      (b.p. 60-80° C.)                    CH.sub.2 CH.sub.2 CH.sub.3                                                                  H   OH B   HCl  *                                               CH.sub.2 CHCH.sub.2                                                                         H   OH B   HCl 150   ethanol-ether                                                           (decomp.)                                         ##STR40##    H   OH B   HCl 226-227                                                                             ethanol-ether                               ##STR41##    H   OH B   HCl  *                                                ##STR42##    H   OH B   HCl  *                                                ##STR43##    H   OH D   oxalate                                                                           200 (decomp.)                                                                       methanol ethyl acetate                                              HCl 203-205                                                                             methanol-ether                              ##STR44##    H   OH D   acetate                                                                           173-176                                                                             ethyl acetate- P.E. (b.p. 80-100.degree                                       . C.)                                       ##STR45##    H   OH F   oxalate                                                                           200 (decomp.)                                                                       methanol-ether                              ##STR46##    H   OH D   oxalate                                                                           165 (decomp.)                                                                       methanol ethyl acetate                      ##STR47##    H   OH D   HCl 152 (decomp.)                                                                       methanol- ether                             ##STR48##    H   OH F   oxalate                                                                           195 (decomp.)                                                                       methanol- ether                             ##STR49##    H   OH D   oxalate                                                                           250                                                                                  ##STR50##                                  ##STR51##    H   OH D   HCl 222-224                                                                             methanol- ether                            CH.sub.3      OH  H  D   Free                                                                              220-230                                                                             ethyl                                                               base      acetate-                                                                      petrol ether                                                                  (b.p. 60-80° C.)                    __________________________________________________________________________      *   Structure determined by mass spectrometry as follows:                               R.sup.1     M.sup.+                                                                          m/e                                                __________________________________________________________________________                CH.sub.2 CH.sub.2 CH.sub.3                                                                309                                                                               99                                                             ##STR52##  335                                                                              125                                                            CH.sub.2CHC(CH.sub.3).sub.2                                                               335                                                                              125                                                __________________________________________________________________________    A. As in Example 4.                                                           B. Excess boron tribromide in methylene chloride is added                     dropwise to a stirred solution of the methyl ether in                         methylene chloride at -5° C. The reaction mixture is                   allowed to reach room temperature and stirred for 2 hours.                    Saturated sodium bicarbonate solution is added and the                        methylene chloride layer is separated, washed with water,                     dried and treated with excess etheral hydrochloric acid.                      The precipitated hydrochloride is recrystallized.                             C. The methyl ether is refluxed in 48% aqueous hydro-                         bromic acid for 30 minutes. Ethyl acetate and then saturated                  sodium bicarbonate solution is added and the organic layer                    seperated, dried and evaporated. The product is re-                           crystallised.                                                                 D. The methyl ether and pyridine hydrochloride are heated                     at 200° C. under nitrogen for 1 hour. The mixture is cooled,           water added, basified with saturated sodium bicarbonate                       solution and extracted with ethyl acetate. The ethyl acetate                  extract is washed with water, dried and evaporated. The                       product is recrystallised.                                                    E. A mixture of the methyl ether and excess sodium                            thioethoxide in dimethylformamide is heated at 100° C. for 4           hours under argon. Water is added to the cooled mixture                       which is then acidified with 3N hydrochloric acid and ex-                     tracted with ether. The aqueous layer is basified with                        saturated sodium bicarbonate solution and extracted with ethyl                acetate. The ethyl acetate extract is washed, dried and                       evaporated. The product is recrystallised.                                    F. A mixture of the methyl ether and excess sodium thio-                      phenoxide in dimethylformamide is heated at 140° C. for 1 hour         under nitrogen. The reaction mixture worked up as in                          example E.                                                                    **    The starting material is obtained by repeating the                            second and first parts of Example 10 using an                                 equivalent amount of cyclobutane carboxylic acid                              chloride in place of cyclopropane carboxylic acid                             chloride and there is thus obtained 1'-cyclobutyl-                            carbonyl-4-methoxyxanthene-9-spiro-4'-piperidine                              and 1'-cyclobutylmethyl-4-methoxyxanthene-9-spiro-4'-                         piperidine hydrochloride, m.p. 225-227° C. on                          recrystallisation from isopropanol/ether, respectively.                 __________________________________________________________________________

EXAMPLE 12

The process described in Example 5 is repeated using an equivalentamount of the appropriate hydroxyxanthene as starting material in placeof 1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine. The followingcompounds are thus obtained:

    ______________________________________                                         ##STR53##                                                                    R.sup.1       Salt    m.p.(° C.)                                                                       Solvent                                       ______________________________________                                         ##STR54##    HCl     214-218                                                                                  ##STR55##                                     ##STR56##    HCl     231-233   ethyl acetate  ether                          ______________________________________                                    

EXAMPLE 13

A mixture of 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (7.5g.), bromine (6 ml.) and chloroform (250 ml.) is heated under reflux for20 hours. The solution is washed with dilute sodium hydroxide solutionand water, dried over MgSO₄, and evaporated to dryness. The solidresidue is dissolved in ethanol and treated with ethereal hydrochloricacid. The solid is recrystallised from ethanol-ether to give1'-methyl-2,7-dibromoxanthene-9-spiro-4'-piperidine hydrochloride, m.p.292°-295° C. (decomp.)

EXAMPLE 14

To a solution of 1'-methylxanthene-9-spiro-4'-piperidine (1.3 g.) inhexane (25 ml.) in an argon atmosphere is added a 1.6 molar solution oft-butyl lithium in pentane (3.5 ml.) with stirring at room temperature.The mixture is stirred for 1 hour at room temperature. Hydroxylaminemethyl ether (0.4 g.) in hexane (5 ml.) is added dropwise during 5minutes. Water is added and the organic layer separated, washed withwater and dried with MgSO₄. The solvent is evaporated to give a solidresidue, which is recrystallised from hexane to give1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine, m.p. 173°-174° C. Theabove process is repeated using an equivalent amount of sulphur andparaformaldehyde as starting material in place of hydroxylamine methylether. The following compounds are thus prepared:

    ______________________________________                                         ##STR57##                                                                    R.sup.1 Salt       m.p.(° C.)                                                                         Solvent                                        ______________________________________                                        SH      oxalate    190-192     methanol-ether                                 CH.sub.2 OH                                                                           Free base  167-169     ether-petroleum                                                               ether                                                                         b.p. 60-80° C.                          ______________________________________                                    

EXAMPLE 15

A mixture of 1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine (0.06 g.)and acetic anhydride (0.5 ml.) in ether (20 ml.) is stirred at roomtemperature for 0.5 hour. The ether solution is washed with saturatedsodium carbonate solution and water, dried with MgSO₄ and the etherevaporated to give a gummy residue. The residue is crystallised fromhexane to give 1'-methyl-4-acetamidoxanthene-9-spiro-4'-piperidine, m.p.176°-178° C.

EXAMPLE 16

A mixture of 1'-(prop-2-ynyl)-4-methoxyxanthene-9-spiro-4'-piperidinehydrogen oxalate (1.3 g.) and pyridine hydrochloride prepared frompyridine (9 ml.) and concentrated hydrochloric acid (10 ml.) is heatedat 200° C. for 10 minutes. The mixture is cooled and water (20 ml.)added. The solution is basified with dilute sodium carbonate solutionand extracted with ether. The ether extract is washed with water, driedwith MgSO₄ and evaporated to dryness. The solid residue isrecrystallised from ethyl acetate-petroleum ether (b.p. 80°-100° C.) togive 1'-(3-chloro-prop-2-enyl)-4-hydroxyxanthene-9-spiro-4'-piperidine,m.p. 153°-155° C.

EXAMPLE 17

The process described in Example 2 is repeated using1'-methylxanthene-9-spiro-4'-piperidin-2',6'-dione in place of1'-methylxanthene-9-spiro-4'-piperidin-2'-one as starting material andthere is thus obtained 1'-methylxanthene-9-spiro-4'-piperidinehydrochloride, m.p. 220°-222° C.

The 1'-methylxanthene-9-spiro-4'-piperidin-2',6'-dione used as startingmaterial may be prepared as follows:

Xanthene (9 g.) is dialkylated as in Example 1 except that allyl bromideis used as alkylating agent instead of N-methyldi-(2-chlorethyl)amine.The crude product is chromatographed on silica gel and9,9-diallylxanthene is eluted with petroleum ether (b.p. 60°-80° C.).The product is obtained as a gum and its structure verified by nuclearmagnetic resonance.

Without further purification, 9,9-diallylxanthene in t-butanol (75 ml.)is added dropwise to a stirred solution of potassium permanganate (0.2g.), sodium metaperiodate (35 g.) and potassium carbonate (10 g.) inwater (250 ml.) and left overnight. The solution is acidified withdilute hydrochloric acid and extracted with ethyl acetate. Xanthene9,9-diacetic acid is extracted from the organic layer with sodiumhydrogen carbonate solution and after recovery by acidificationrecrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.),m.p. 187°-188° C.

A solution of xanthene 9,9-diacetic acid (0.8 g.) in acetic anhydride (3ml.) is heated under reflux for 1 hour, cooled and poured into water.Extraction with ethyl acetate givesxanthene-9-spiro-4'-tetrahydropyran-2',6'-dione which is recrystallisedfrom ethyl acetate-petroleum ether (b.p. 60°-80° C.), m.p. 188°-190° C.

This anhydride is treated with excess aqueous methylamine at roomtemperature. After ten minutes, the solution is acidified with dilutehydrochloric acid and the monoacid-monoamide is filtered and dried.Without further purification it is treated with excess acetic anhydrideat reflux for 0.5 hours, and the reaction mixture then poured into coldaqueous sodium bicarbonate. The product, extracted with ethyl acetate,is chromatographed on silica gel and eluted with 2% ethylacetate-petroleum ether (b.p. 60°-80° C.), giving1'-methylxanthene-9-spiro-4'-piperidin-2',6'-dione which isrecrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.),m.p. 148°-149° C.

EXAMPLE 18

A mixture of 4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride (0.69g.), propargyl bromide (0.24 g.), potassium carbonate (0.4 g.) or sodiumhydride (0.12 g. of an 80% w/w dispersion in oil) and dimethylformamide(10 ml.) is stirred at room temperature for 3 hours. The mixture ispoured into water and extracted with ethyl acetate. The ethyl acetateextract is washed with water, dried with MgSO₄ and evaporated to give agummy residue. The residue is dissolved in ether and the precipitateobtained on treatment with ethereal hydrochloric acid recrystallisedfrom ethanol-ether to give4-acetoxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride,m.p. 118°-120° C.

The above process is repeated using equivalent amounts of theappropriate alkylating halide, and the following are thus obtained:

    ______________________________________                                         ##STR58##                                                                    R           Salt      m.p.(° C.)                                                                      Halide                                         ______________________________________                                        CH.sub.2 COCH.sub.3                                                                       HCl 1/4 H.sub.2 O                                                                       252-254  ClCH.sub.2 COCH.sub.3                          CH.sub.2 CONHMe                                                                           HCl       233-236  BrCH.sub.2 CONHMe                              CH.sub.2 CHCH.sub.2                                                                       HCl       225-227  BrCH.sub.2 CHCH.sub.2                          CH.sub.2 CONMe.sub.2                                                                      HCl 3/4 H.sub.2 O                                                                       210-213  BrCH.sub.2 CONMe.sub.2                         ______________________________________                                    

The 4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride used asstarting material may be prepared in the following way:

1'-Benzyl-4-methoxyxanthene-9-spiro-4'-piperidine is demethylated using45% w/v hydrobromic acid in glacial acetic acid as described in Example4 to give 1'-benzyl-4-hydroxyxanthene-9-spiro-4'-piperidine converted toits hydrochloride, m.p. 164° C. on recrystallisation from ethanol-ether.

The 1'-benzyl-4-hydroxyxanthene-9-spiro-4'-piperidine is acetylatedusing acetic anhydride in pyridine as described in Example 5 to give4-acetoxy-1'-benzylxanthene-9-spiro-4'-piperidine hydrochloride, m.p.234°-236° C. on recrystallisation from ethanol-ether.

A solution of 4-acetoxy-1'-benzylxanthene-9-spiro-4'-piperidinehydrochloride (13.5 g.) in ethanol (200 ml.) is hydrogenated using 5%w/w palladium-on-carbon catalyst, at 1 atmosphere and 25° C. Thecatalyst is filtered off and the solvent evaporated to dryness. Theresidue is crystallised from ethanol-ether to give4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 162°-165° C.

EXAMPLE 19

The quaternary chloride1',1'-dimethyl-4-methoxyxanthene-9-spiro-4'-piperidinium chloride isheated at 200°-220° C. under vacuum (0.1 mm.) for 1 hour. The cooledresidue is dissolved in methanol, poured into water and extracted withether. The dried ether solution is treated with anhydrous etherealhydrochloric acid to give4-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p.232°-235° C.

The quaternary chloride used as starting material may be prepared asfollows:

9,9-Bis-(2'-methanesulphonyloxyethyl)-4-methoxyxanthene (0.5 g.) istreated with excess ethanolic dimethylamine at reflux for 2 hours. Thesolution is evaporated to dryness and the residue triturated withtoluene. The solid quaternary salt,1',1'-dimethyl-4-methoxyxanthene-9-spiro-4'-piperidiniummethanesulphonate dihydrate is recrystallised from methanol-ether, m.p.215°-220° C.

The quaternary methanesulphonate (0.1 g.) is dissolved in methanol andpassed down a strongly basic (quaternary amine) ion exchange column inthe chloride form. The eluant is evaporated to dryness to give1',1'-dimethyl-4-methoxyxanthene-9-spiro-4'-piperidinium chloride whichis used without further purification.

EXAMPLE 20

4-Acetoxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride(0.4 g.) is stirred with 3N hydrochloric acid (20 ml.) at roomtemperature for 24 hours. The solution is basified using solid sodiumbicarbonate and extracted with ethyl acetate. The ethyl acetate extractis dried over MgSO₄ and evaporated to give a gummy residue which isdissolved in ether and treated with ethereal hydrochloric acid. Theprecipitate is recrystallised from ethanol-ether to give4-hydroxy-1'-(prop-2-ynyl)xanthene-9-spiro-4'-piperidine hydrochloride,m.p. 246°-247° C.

The above process is repeated using the appropriate 4-acetoxyxanthenederivative as starting material and the following compounds are thusobtained:

    ______________________________________                                         ##STR59##                                                                                                  Recrystallisation                               R           Salt     m.p.(°C.)                                                                       solvent                                         ______________________________________                                        CH.sub.2 CONHMe                                                                           HCl H.sub.2 O                                                                          168      ethyl acetate                                   CH.sub.2 CONMe.sub.2                                                                      HCl H.sub.2 O                                                                          184-186  ethyl acetate                                   ______________________________________                                    

EXAMPLE 21

A mixture of 4-hydroxy-1-methyl-4-(2'-phenoxy)phenylpiperidine (0.5 g.)and polyphosphoric acid (5 g.) is heated on a steam-bath for 1 hour. Themixture is poured into 10N ammonium hydroxide solution and extractedwith chloroform. The chloroform extract is dried with MgS0₄ andevaporated to give a gummy residue which is dissolved in ether andtreated with ethereal hydrochloric acid. The precipitate obtained isrecrystallised from ethanol-ether to give1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 221°-223° C.

The 4-hydroxy-1-methyl-4-(2'-phenoxy)phenylpiperidine used as startingmaterial may be prepared as follows:

A solution of n-butyl lithium in hexane (2.25M., 45 ml.) is slowly addedto a solution of diphenyl ether (8.5 g.) in sodium dried diethyl ether(200 ml.) under an atmosphere of argon. The mixture is stirred for 24hours at room temperature, cooled to 0° C. and a solution of1-methyl-4-piperidone (5.7 g.) in diethyl ether (25 ml.) is slowlyadded. The mixture is stirred at room temperature for 24 hours. Water isthen carefully added and the organic layer is separated, dried withMgS0₄ and evaporated to give a white solid which is recrystallised fromether to give 4-hydroxy-1-methyl-4-(2'-phenoxy(phenylpiperidine, m.p.118°-119° C.

EXAMPLE 22

A mixture of4-methoxy-1'-methyl-6-(methylthio)xanthene-9-spiro-4'-piperidine (0.5g.) and aqueous sodium metaperiodate (5 ml. of 0.5M solution) is stirreduntil a solution is obtained. The reaction mixture is added to aqueoussodium bicarbonate and extracted with ethyl acetate. The ethyl acetateis evaporated and the organic basic residue is converted to itshydrochloride to give4-methoxy-1'-methyl-6-methylsulphinylxanthene-9-spiro-4'-piperidinehydrochloride, m.p. 183°-185° C. on recrystallisation fromethanol-ether.

The 4-methoxy-1'-methyl-6-(methylthio)xanthene-9-spiro-4'-piperidineused as starting material may be prepared as follows:

A suspension of 3-chloro-5-methoxyxanthone (5 g.) in dimethylformamideis added to a solution of excess sodium thiomethoxide indimethylformamide (prepared from methyl mercaptan and sodium hydride).After 1 hour the reaction mixture is poured into water and extractedwith ether, giving on evaporation 5-methoxy-3-(methylthio)xanthone, m.p.201°-203° C. on recrystallisation from methanol.

The process described in Example 34 is repeated using5-methoxy-3-(methylthio)xanthone as starting material to give5-methoxy-3-(methylthio)xanthene which is recrystallised from methanoland characterised by its infra-red spectrum. The process described inExample 25 is then repeated using 5-methoxy-3-(methylthio)xanthene asstarting material and there is thus obtained4-methoxy-1'-methyl-6-(methylthio)xanthene-9-spiro-4'-piperidinehydrochloride, m.p. 112°-114° C. on recrystallisation fromethanol-ether.

EXAMPLE 23

The process described in Example 22 is repeated using an equivalentamount of4-hydroxy-1'-methyl-6-(methylthio)xanthene-9-spiro-4'-piperidine asstarting material and there is thus obtained4-hydroxy-1'-methyl-6-methylsulphinylxanthene-9-spiro-4'-piperidinehydrochloride hemihydrate, m.p. 282°-283° C.

EXAMPLE 24

A solution of4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidinehydrochloride (1.5 g.) in ethanol (200 ml.) is hydrogenated using 5% w/wpalladium-on-carbon catalyst at 1 atmosphere and 25° C. The catalyst isfiltered off and the ethanol evaporated to give a gummy residue which iscrystallised from ethanol-ether to give4-hydroxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidinehydrochloride, m.p. 223°-224° C.

The 4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine usedas starting material may be prepared as follows:

To a solution of 3-chloro-5-methoxyxanthone (12.5 g.) [see Examples 32and 33] in dry dichloromethane at 0° C. is slowly added boron tribromide(24 ml.). The mixture is stirred at room temperature for 24 hours, thenpoured into water. The resulting precipitate if filtered off and driedto give 3-chloro-5-hydroxyxanthone which is used without furtherpurification.

The 3-chloro-5-hydroxyxanthone (11 g.) in dimethylformamide (50 ml.) isadded to a suspension of sodium hydride (1.5 g.) in dimethylformamide(100 ml.). The mixture is stirred at room temperature for 15 minutes andbenzyl bromide (6 ml.) is added dropwise. The mixture is poured intowater/ice (600 ml.), extracted with chloroform and the chloroformextract dired with MgS0₄. Evaporation of the solvent gives a light-brownsolid which is recrystallised from ethanol to give5-benzyloxy-3-chloroxanthone, m.p. 154° C.

A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3g.), methanol (20 ml.) and dimethylformamide (100 ml.) is stirred atroom temperature for 24 hours. The mixture is poured into water and theprecipitate is filtered. The residue is recrystallised from isopropanolto give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.

5-Benzyloxy-3-methoxyxanthone (3.5 g.) is reduced using a solutionborane-tetrahydrofuran complex as described in Example 34 to give5-benzyloxy-3-methoxyxanthene, m.p. 107°-108° C. on recrystallisationfrom methanol.

5-Benzyloxy-3-methoxyxanthene is reacted withN-methyldi-(2-chloroethyl)amine using the method described in Example 1to give 4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidinehydrochloride which is used without further purification.

EXAMPLE 25

The process described in Example 1 is repeated using the equivalentamount of the appropriate substituted xanthene as starting materialinstead of xanthene. The following compounds are thus obtained:

    ______________________________________                                         ##STR60##                                                                    R.sup.2     R.sup.3  Salt         m.p. (° C.)                          ______________________________________                                        4-OMe     6-OMe      HCl 1 H.sub.2 O                                                                            138-139                                     4-OMe     6-Cl       HCl 2 H.sub.2 O                                                                            154-157                                     4-OMe     7-CF.sub.3 HCl          295-296                                     4-OMe     6-SMe      HCl          112-113                                     4-OMe     2-Cl       HCl          265-268                                     2,3-diCl  H          oxalate      183-185                                      ##STR61##                                                                              H          HCl 1/4 H.sub.2 O                                                                          208-210                                     3-Cl      H          maleate      174-176                                     4-OMe     6-F        HCl 1 H.sub.2 O                                                                            114-117                                     4-OMe     7-F        HCl 1/4 H.sub.2 O                                                                          252-255                                     4-OMe     8-F        HCl 1/4 H.sub.2 O                                                                          195-200 *                                   ______________________________________                                        *       Recrystallised from isopropanol-ether.                                ______________________________________                                    

EXAMPLE 26

A mixture of 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine (370 mg.),ethanol (80 ml.) and a 50% w/v solution of potassium hydroxide in water(20 ml.) is heated under reflux for 22 hours. The mixture is cooled andconcentrated hydrochloric acid (20 ml.) is added and the ethanol isevaporated. The residue is washed with ether, water (50 ml.) is addedand the resulting solution made alkaline with 3N sodium hydroxide. Thealkaline solution is extracted with chloroform and the chloroformextract is washed with water, dried (MgSO₄) and evaporated to dryness.The gummy residue is dissolved in ethanol and treated with etherealhydrochloric acid. The solid is recrystallised from ethanol-ether togive xanthene-9-spiro-4'-piperidine hydrochloride, m.p. 248°-250° C.

The 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine used as startingmaterial may be obtained as follows:

A solution of phenyl chloroformate (8 ml.) in methylene chloride (75ml.) is added dropwise with stirring to a solution of1'-methylxanthene-9-spiro-4'-piperidine (17.0 g.) in methylene chloride(200 ml.) at 5° C. The mixture is allowed to reach room temperature andstirred overnight. The mixture is washed successively with 3N sodiumhydroxide solution, 3N hydrochloric acid and water, dried (MgS0₄) andthe methylene chloride evaporated to dryness. The gummy residue iscrystallised from methanol to give1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine, m.p. 105°-107° C.

EXAMPLE 27

A mixture of xanthene-9-spiro-4'-piperidine hydrochloride (1 g.),potassium carbonate (1.2 g.) and γ-chloro-p-fluorobutyrophenone ethyleneketal (1.03 g.) in n-butanol is heated under reflux for 48 hours. Themixture is poured into water, extracted with ether, the ether solutionevaporated and the residue warmed with 3N hydrochloric acid for 1 hourto hydrolyse the ketal. The acidic solution is extracted with ethylacetate, the solvent evaporated and the residue recrystallised fromethyl acetate to give1'-[3-(p-fluorobenzoyl)propyl]xanthene-9-spiro-4'-piperidinehydrochloride (0.51 g.), m.p. 219°-222° C.

EXAMPLE 28

A mixture of 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (5g.), N-chlorosuccinimide (4.5 g.) and dichloromethane (100 ml.) isrefluxed for 72 hours. The solution is washed with saturated sodiumbicarbonate solution then water and dried with MgS0₄. The solution isevaporated to give a gummy residue which is chromatographed on grade 3aluminium oxide, Woelm basic. The product is eluted with 30%petroleum-ether (b.p. 60°-80° C.)/chloroform, taken up in ether and thesolution treated with ethereal hydrochloric acid. The precipitate isfiltered and recrystallised from ethanol-ether to give2,7-dichloro-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p.285° C.

EXAMPLE 29

The following compounds are prepared by repeating the process describedin Example 7 using the appropriate dimethanesulphonate and appropriateamine as starting materials:

    __________________________________________________________________________     ##STR62##                                                                                              Recrystallisation                                   R.sup.1   R.sup.2                                                                           R.sup.3                                                                         Salt                                                                              m.p. (° C.)                                                                   solvent                                            __________________________________________________________________________     ##STR63##                                                                              OCH.sub.3                                                                         Cl                                                                              HCl 245-248                                                                             ethanol-ether                                        ##STR64##                                                                              OCH.sub.3                                                                         Cl                                                                              HCl 274-277                                                                             ethanol-ether                                       CH.sub.3  OCH.sub.3                                                                         Cl                                                                              HCl 248-252                                                                             isopropanol-                                                                  ether                                               CH.sub.2 CONH.sub.2                                                                     H   H HCl 266   ethanol-ether                                                           (decomp.)                                                 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     H   H 2 HCl-                                                                        2 H.sub.2 O                                                                       265-268                                                                             ethanol                                             __________________________________________________________________________

The 2-chloro-9,9-di-(2-methanesulphonyloxyethyl)-5-methoxyxanthene usedas starting material may be prepared as follows:

The second part of Example 2 is repeated using2-chloro-5-methoxyxanthene as starting material in place of xanthene.The second and third parts of Example 3 are then repeated using thebis-vinyloxyethyl derivative obtained immediately above as startingmaterial. There are thus obtained9,9-bis-(2-hydroxyethyl)-2-chloro-5-methoxyxanthene, m.p. 192°-195° C.on recrystallisation from toluene and2-chloro-9,9-di-(2-methanesulphonyloxyethyl)-5-methoxyxanthene, m.p.165°-167° C. on recrystallisation from toluene-petroleum ether (b.p.60°-80° C.), respectively.

EXAMPLE 30

One of the demethylation processes described in Example 11 is repeatedusing the appropriate methoxyxanthene derivative as starting material,and the following compounds are thus obtained:

    __________________________________________________________________________     ##STR65##                                                                                                    Recrystall-                                                                   isation                                        R.sup.1  R.sup.2                                                                         R.sup.3                                                                           Method                                                                            Salt  m.p. (° C.)                                                                  solvent                                       __________________________________________________________________________     ##STR66##                                                                              H 7-Cl                                                                              B   HCl H.sub.2 O                                                                        *                                                  CH.sub.3  H 6-Cl                                                                              C   HCL 1/4 H.sub.2 O                                                                   265-267                                                                             ethanol-                                                                      ether                                         CH.sub.3  H 6-OH                                                                              C   HCl 3/4 H.sub.2 O                                                                   283-284                                                                             ethanol-                                                                      ether                                          ##STR67##                                                                              H 7-Cl                                                                              B   HCl 1/2 H.sub.2 O                                                                    *                                                  CH.sub.3  H 7-CF.sub.3                                                                        C   HCl 1/2 H.sub.2 O                                                                   188   ethyl                                                                         acetate                                       CH.sub.2 CH(OH)CH.sub.3                                                                 H 7-Cl                                                                              B   HCl    *                                                  CH.sub.3  H 6-SCH.sub.3                                                                       B   HCl   276-277                                                                             ethanol-                                                                      ether                                         CH.sub.3  Cl                                                                              H   C   HCl   268-272                                                                             ethyl                                                                         acetate-                                                                      ether                                         CH.sub.3  H 6-F B   HCL 1/2 H.sub.2 O                                                                   259-260                                                                             ethanol-                                                                (decomp.)                                                                           ether                                         CH.sub.3  H 7-F C   HCl 1/2 H.sub.2 O                                                                   242-244                                                                             ethyl                                                                         acetate                                       CH.sub.3  H 8-F C   HCl   >300  isopropanol-                                                                  ether                                         CH.sub.3  H 7-Cl                                                                              C   HCl   183-184                                                                             isopropanol-                                                            (decomp.)                                                                           ether                                         CH.sub.2 CH.sub.2 OH                                                                    H H   E   HCl   248   ethyl                                                                         acetate                                       CH.sub.2 CH(OH)CH.sub.3                                                                 H H   B   HCl H.sub.2 O                                                                       199-201                                                                             ethanol                                                                       ether                                         __________________________________________________________________________    *     non-crystalline glasses - structures confirmed by micro-                      analysis, and by mass spectrometry as follows:                                      R.sup.1  M.sup.+                                                                          m/e                                                   __________________________________________________________________________              ##STR68##  355                                                                              111                                                             ##STR69##  369                                                                              125                                                             ##STR70##  359                                                                              115                                                   __________________________________________________________________________

EXAMPLE 31

The process described in Example 5 is repeated using an equivalentamount of the appropriate hydroxyxanthene as starting material in placeof 4-hydroxy-1'-methylxanthene-9-spiro-4'-piperidine. The followingcompounds are thus obtained:

    __________________________________________________________________________     ##STR71##                                                                                                 Recrystallisation                                 R.sup.1     R.sup.2                                                                            Salt m.p. (° C.)                                                                   solvent                                         __________________________________________________________________________    Me           7-Cl                                                                              HCl   *     isopropanol-                                                                  ether                                            Me           6-Cl                                                                              HCl 2 H.sub.2 O                                                                     146-147                                                                             isopropanol-                                                                  ether                                            Me           6-SMe                                                                             HCl 1 H.sub.2 O                                                                     *     ethanol-ether                                    Me           6-OMe                                                                             HCl 1/2 H.sub.2 O                                                                   237-238                                                                             ethyl acetate                                                           (decomp.)                                              Me           6-F HCl 2 H.sub.2 O                                                                     212-214                                                                             ethyl acetate                                     ##STR72##   H   HCl 1/2 H.sub.2 O                                                                   244-245                                                                             ethanol-ether                                     ##STR73##   H   HCL 1 H.sub.2 O                                                                     202-204                                                                             ethanol-ether                                    Me           6-OAc                                                                             HCl 1/2 H.sub.2 O                                                                   149-151                                                                             ethanol-ether                                    __________________________________________________________________________    *     non-crystalline glasses - structures confirmed by micro-                      analysis, and mass spectrometry as follows:                                                 R.sup.1                                                                         R.sup.2                                                                           M.sup.+                                             __________________________________________________________________________                        Me                                                                              7-Cl                                                                              357                                                                     Me                                                                              6-SMe                                                                             369                                                 __________________________________________________________________________

The process described in Example 5 is also repeated using an equivalentamount of the appropriate 4-hydroxyxanthene as starting material inplace of 4-hydroxy-1'-methylxanthene-9-spiro-4'-piperidine and theappropriate acid chloride in place of acetic anhydride. The followingcompounds are thus prepared as their hydrochlorides:

    ______________________________________                                         ##STR74##                                                                                                    Recrystallisation                             R.sup.2        R.sup.3                                                                              m.p. (° C.)                                                                       solvent                                      ______________________________________                                         ##STR75##     H      230-231   ethyl acetate                                  ##STR76##     6-Cl   262       ethanol-ether                                  ##STR77##     7-Cl    **       ethanol-ether                                  ##STR78##     H      152-155   isopropanol-ether                             SO.sub.2 CH.sub.3                                                                            H      230-235   ethyl acetate                                                       (decomp.)                                               ______________________________________                                    

EXAMPLE 32

A mixture of 2,5-dichlorobenzoic acid (9.5 g.), 2-methoxyphenol (7.4 g.)and copper bronze (1.0 g.) is added to a solution of sodium methoxide inmethanol prepared from sodium (2.53 g.) and methanol (50 ml.). Theexcess methanol is evaporated and 1,2-dichlorobenzene (50 ml.) is addedto the residue. The mixture is stirred and heated under reflux for 2.5hours. The mixture is cooled, acidified with 3N hydrochloric acid,filtered to remove copper bronze and extracted with chloroform. Theorganic layer is separated and extracted with saturated sodium hydrogencarbonate solution. The sodium hydrogen carbonate extract is acidified.The precipitate is filtered off, dissolved in toluene, and the toluenesolution treated with carbon, filtered and the solvent evaporated. Thesolid residue is recrystallised from toluene-petroleum ether (b.p.60°-80° C.) to give 5-chloro-2-(2'-methoxyphenoxy)benzoic acid, m.p.115°-118° C.

The above process is repeated using equivalent amounts of theappropriate 2-chlorobenzoic acid in place of 2,5-dichlorobenzoic acidand the appropriate substituted phenol in place of 2-methoxyphenol asstarting materials and copper bronze or copper bronze with a trace ofcuprous iodide as the catalyst. The following compounds are thusobtained:

    ______________________________________                                         ##STR79##                                                                                                       Recrystallisation                          R.sup.1                                                                            R.sup.2  R.sup.3 R.sup.4                                                                            m.p. (° C.)                                                                     solvent                                   ______________________________________                                        H    2'-OMe   4-Cl    H    *       methanol-water                             H    2'-OMe   5-CF.sub.3                                                                            H    115-116 methanol-water                             H    2'-OMe   6-F     H    147-150 ethyl acetate-                                                                petroleum ether                                                               (b.p. 60-80° C.)                    4'-Cl                                                                              2'-OMe   H       H    161-163 toluene                                    H    H        4-Cl    5-Cl 156-158 toluene                                    H    2'-OMe   4-F     H    *       isopropanol                                ______________________________________                                         * Compound characterised by its infra-red spectrum.                      

EXAMPLE 33

A mixture of 5-chloro-2-(2'-methoxyphenoxy(benzoic acid (15 g.) andpolyphosphoric acid (75 g.) is heated on a steam-bath for 3 hours. Themixture is poured into 10N ammonium hydroxide solution and theprecipitate is filtered, dried and recrystallised from toluene to give3-chloro-5-methoxyxanthone, m.p. 201°-202° C.

The above process is repeated using the appropriate substituted benzoicacid to prepare the following compounds:

    ______________________________________                                         ##STR80##                                                                                                     Recrystallisation                            R.sup.1                                                                              R.sup.2  R.sup.3  m.p. (° C.)                                                                     solvent                                     ______________________________________                                        2-Cl   H        5-OMe    194-195 toluene                                      2-CF.sub.3                                                                           H        5-OMe     *      methanol                                     1-F    H        5-OMe    219-220 toluene                                      2-Cl   H        4-OMe    209-210 methanol                                     2-Cl   3-Cl     H        174-175 toluene                                      3-F    H        5-OMe    178     isopropanol                                  ______________________________________                                         * This compound is characterised by its infra-red spectrum.              

EXAMPLE 34

A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M., 38ml.) is added slowly to a solution of 3-chloro-5-methoxyxanthone (15 g.)in tetrahydrofuran (200 ml.). The mixture is refluxed for 2 hours,cooled to room temperature and poured into water. The precipitate isfiltered, dried and recrystallised from methanol to give3-chloro-5-methoxyxanthene, m.p. 106°-108° C.

The above process is repeated using the appropriate xanthone to preparethe following compounds:

    ______________________________________                                         ##STR81##                                                                                                     Recrystallisation                            R.sup.1                                                                              R.sup.2  R.sup.3  m.p. (° C.)                                                                     solvent                                     ______________________________________                                        2-Cl   H        5-OMe    105-106 methanol                                     2-CF.sub.3                                                                           H        5-OMe    138-139 methanol                                     1-F    H        5-OMe    105-107 methanol                                     2-Cl   H        4-OMe    83-84   methanol                                     2-Cl   3-Cl     H        *       methanol                                     3-F    H        5-OMe    *       isopropanol                                  3-OMe  H        5-OMe    135-136 methanol-water                               2-F    H        5-OMe    **      methanol                                     3-SMe  H        5-OMe    *       methanol                                     ______________________________________                                          * This compound is characterised by its infra-red spectrum.                  ** This compound is characterised by mass spectrometry.                  

EXAMPLE 35

2-Methoxyphenol (5.0 g.) is added to a stirred mixture of sodium hydride(1.2 g. of a 80% w/w dispersion in mineral oil) and dimethylsulphoxide(50 ml.). When evolution of hydrogen is complete, a solution of thepotassium salt of 2-chloro-5-nitrobenzoic acid (5.0 g.) indimethylsulphoxide (20 ml.) is added and the mixture is stirred andheated on the steam-bath overnight.

The mixture is cooled and poured into excess 3N hydrochloric acid. Thegummy precipitate is extracted with chloroform. The chloroform extractis extracted with saturated sodium hydrogen carbonate solution.Acidification of the sodium hydrogen carbonate extract gives a solidprecipitate. This precipitate is recrystallised from methanol-water togive 2-(2'-methoxyphenoxy)-5-nitrobenzoic acid, m.p. 162°-165° C.

The process described in Example 33 is then repeated using theequivalent amount of 2-(2'-methoxyphenoxy)-5-nitrobenzoic acid in placeof 4-chloro-2-(2'-methoxyphenoxy)benzoic acid. There is thus obtained5-methoxy-2-nitroxanthone, m.p. 224°-226° C. on recrystallisation fromdimethylformamide.

5-Methoxy-2-nitroxanthone (5.0 g.) is added in small portions during 30minutes to a stirred mixture of stannous chloride dihydrate (30 g.) andconcentrated hydrochloric acid (30 ml.) heated on a steam-bath. Themixture is stirred and heated on a steam-bath for a further 2 hours. Theprecipitate is filtered off, washed with water and stirred with 5Nsodium hydroxide solution (50 ml.) for 1 hour. The solid is filteredoff, made into a slurry with methanol and treated with etherealhydrochloric acid. The solid is crystallised from methanol-ether to give2-amino-5-methoxyxanthone hydrochloride, m.p. 271°-273° C.

A solution of sodium nitrite (3.6 g.) in water (100 ml.) is addeddropwise with stirring to a mixture of 2-amino-5-methoxyxanthone (10.8g.), water (160 ml.) and concentrated hydrochloric acid (25 ml.) at 0°C. After the addition is complete the mixture is stirred for a further10 minutes at 0° C. Urea is added to destroy excess nitrous acid and 40%w/v fluoroboric acid solution (25 ml.) is added and the mixture stirredfor 15 minutes at 5° C. The precipitate is filtered off, washed withcold ethanol and ether and air dried to give 5-methoxy-2-xanthonyldiazonium tetrafluoroborate which is used without further purification.

The 5-methoxy-2-xanthonyl diazonium tetrafluoroborate (11.6 g.) isheated at 200° C. for 30 minutes. The residue is chromatographed onsilica gel, eluting with chloroform. The solid obtained on evaporationof the solvent is recrystallised from methanol to give2-fluoro-5-methoxyxanthone, m.p. 170°-172° C.

What we claim is:
 1. A method of relieving or preventing pain in warmblooded animals including man, which comprises administering ananalgesically-effective amount of a compound of the formula: ##STR82##wherein R¹ is selected from the group consisting of
 1. hydrogen;2. alkylof 1 to 10 carbons;
 3. alkenyl of 3 to 10 carbons wherein the doublebond it contains is separated from the nitrogen atom of thespiropiperidine ring by at least one carbon;
 4. haloalkenyl of 3 to 6carbons wherein the double bond it contains is separated from thenitrogen atom of the spiropiperidine ring by at least one carbon; 5.alkynyl of 3 to 6 carbons wherein the triple bond it contains isseparated from the nitrogen atom of the spiropiperidine ring by at leastone carbon;
 6. cycloalkylalkyl of 4 to 7 carbons, optionally substitutedin the cycloalkyl nucleus by an aryl radical of 6 to 10 carbons or byone or two alkyls of 1 to 3 carbons;7. phenyl;
 8. arylalkyl of 7 to 10carbons, optionally substituted in the aryl nucleus by one to threehalogens or alkyls of 1 to 3 carbons;
 9. aroylalkyl of 8 to 12 carbons,optionally substituted in the aryl nucleus by one to three halogens oralkyls of 1 to 3 carbons;
 10. hydroxyalkyl of 2 to 5 carbons wherein theoxygen atom it contains is separated from the nitrogen atom of thespiropiperidine ring by at least two carbons;
 11. dialkylaminoalkyl of 4to 8 carbons wherein the nitrogen atom it contains is separated from thenitrogen atom of the spiropiperidine ring by at least two carbons; 12.carbamoylalkyl of 2 to 8 carbons;
 13. alkylcarbamoylalkyl of 3 to 8carbons;
 14. dialkylcarbamoylalkyl of 4 to 8 carbons; and 15.alkanoylalkyl of 3 to 8 carbons; R², R³, R⁴ and R⁵, which may be thesame or different, are selected from the group consisting of 16.hydrogen;17. halogen;
 18. alkyl of 1 to 5 carbons;
 19. haloalkyl of 1 to5 carbons;
 20. alkoxy of 1 to 5 carbons;
 21. alkylthio of 1 to 5carbons;
 22. hydroxy;
 23. thiol;
 24. alkanoylamino of 1 to 5 carbons;25. alkanoyloxy of 1 to 5 carbons;
 26. aroyloxy of 7 to 10 carbons,optionally substituted in the aryl nucleus by one to three halogens oralkyls of 1 to 3 carbons;
 27. arylalkenoyloxy of 9 to 12 carbons; 28.hydroxyalkyl of 1 to 5 carbons;
 29. alkylsulphinyl of 1 to 5 carbons;and
 30. alkanesulphonyloxy of 1 to 5 carbons; and thepharmaceutically-acceptable acid-addition salts thereof.
 2. The methodof claim 1 wherein R¹ stands for value 1 or 2, R² stands for value 20,21, 22, 23, 25 or 26 substituted at the 4-position and R³, R⁴ and R⁵stand for hydrogen.
 3. The method of claim 1 wherein R¹ stands for value2, 3, 6, 8, 9, 10, 11, 12, 13 or 14, R² stands for chlorine or bromineor methyl, trifluoromethyl, methoxy, methylthio or 1-hydroxyethylsubstituted at the 2- or 3- position, and R³, R⁴ and R⁵ stand forhydrogen.
 4. The method of claim 1 wherein R² stands for value 20, 21,22, 23, 24, 25, 26 or 27 substituted at the 4-position, R⁴ stands forvalue 17, 18, 19, 20, 21, 22 or 29 substituted at the 6-, 7- or 8-position and R³ and R⁵ are both hydrogen.
 5. The method of claim 1wherein R¹ stands for methyl, R² stands for methoxy, hydroxy or acetoxysubstituted at the 4-position, R⁴ stands for fluorine, chlorine,methoxy, methylthio, hydroxy or methylsulphinyl substituted at the6-position or fluorine or chlorine substituted at the 7- or 8-position,and R³ and R⁵ stand for hydrogen. -
 6. The method of claim 1 wherein R¹stands for methyl, R² stands for methoxy, hydroxy or acetoxy substitutedat the 4-position, R³ stands for hydrogen and R⁴ and R⁵, which may bethe same or different, stand for fluorine or chlorine.
 7. The method ofclaim 1 wherein R¹ stands for methyl, R² stands for hydroxy substitutedat the 4-position, R⁴ stands for chlorine substituted at the 6-positionand R³ and R⁵ stand for hydrogen.
 8. A xanthene derivative of theformula: ##STR83## wherein R¹ stands for methyl, R² stands for hydroxysubstituted at the 4-position, R⁴ stands for chlorine substituted at the6-position and R³ and R⁵ stand for hydrogen.